In recent years, a large number and variety of peptide agents such as peptides, oligopeptides, polypeptides, and proteins have been discovered and have received much attention as drug candidates. However, many peptide agents are not stable as they are easily hydrolyzed or degraded in vivo by enzymes resulting in a very short circulation half-life. Therefore, most of peptide medicines have been administered by injection, typically multiple times per day.
Injection administration, however, is painful, very costly, and inconvenient. Often, the patient compliance is very challenging. For many peptide agents, particularly hormones, it requires the drug to be delivered continuously at a controlled rate over a long period of time, and thus a controlled release delivery system is desirable. Such systems may be provided by incorporating the peptide agents in biodegradable and biocompatible polymer matrices. In one approach the polymer is dissolved in an organic solvent and then mixed with the peptide agents that is fabricated into the forms of microcapsules, microgranules or implantable rods by removing the organic solvent. The peptide agent is entrapped within the polymer matrices. Several products have been successfully developed by using biodegradable polymers in the forms of microparticles and solid rod implants, such as Lupron, Zoladex, Triptorelin, etc. Although these products appear to be effective, but they have drawbacks and limitations, such as the large volume of suspending fluids for microparticles or surgical insertion of solid implants. These products are not very patient friendly. In addition, the manufacturing processes for producing sterile and reproducible products are complicated, resulting in high cost of manufacturing. It is highly desirable that a composition can be manufactured and used easily.
In another approach, the biodegradable polymer and the peptide agents are dissolved in a biocompatible organic solvent to provide a liquid composition. When the liquid composition is injected into the body, the solvent dissipates into the surrounding aqueous environment, and the polymer forms a solid or gel depot from which the bioactive agent is released over a long period of time. The following references U.S. Pat. Nos. 6,565,874; 6,528,080; RE37, 950; 6,461,631; 6,395,293; 6,355,657; 6,261,583; 6,143,314; 5,990,194; 5,945,115; 5,792,469; 5,780,044; 5,759,563; 5,744,153; 5,739,176; 5,736,152; 5,733,950; 5,702,716; 5,681,873; 5,599,552; 5,487,897; 5,340,849; 5,324,519; 5,278,202; 5,278,201; and 4,938,763 are believed to be representative in this area and are incorporated herein by reference. Notwithstanding some success, those methods have not been entirely satisfactory for a large number of peptide agents that may be effectively delivered by such an approach.
It is well recognized in the art that bioactive agent containing basic functional groups interacts with biodegradable polymer to catalyze (or expedite) the degradation of the polymer and form conjugate with the polymer and/or its degradation products. The interaction/reaction between the basic bioactive agents and polymer carriers may occur: 1) during formulation when the basic bioactive agents are incorporated in the polymer carrier, such as microencapsulation, injection molding, extrusion molding, mixing with polymer solutions in organic solvent, and the like; 2) during storage and 3) during the process of biodegradation and the release of bioactive agents in vivo.
It is known that the degradation of peptide agents and biodegradable polymers, and reactions between the two typically occur much faster in solution than in a dry, solid state. The interaction/reaction between bioactive agents containing basic functional groups, i.e., amines, and polymers during the microparticle formation process using solvent evaporation/extraction methods where the bioactive agent and polymer were dissolved/dispersed in non-polar organic solvents were disclosed [Krishnan M. and Flanagan D R., J Control Release. 2000 Nov. 3; 69(2): 273-81]. Significant amount of amide moieties were formed. It was clearly shown that commonly used solvents for fabrication of biodegradable polymer drug delivery systems could permit rapid reaction between bioactive agent and polymer. In another disclosure, the accelerated degradation of polymers by organic amines in polar protic organic solvent (e.g., methanol) was also reported [Lin W J, Flanagan D R, Linhardt R J. Pharm Res. 1994 July; 11(7):1030-4].
Since the controlled release delivery system is commonly fabricated through a step that involves dissolving/dispersing peptide agent into biodegradable polymer solution in an organic solvent, the stabilization of all the components in the composition at this step represents a very significant formulation challenge. One common approach that has been used to overcome the challenge of manufacturing and storage stability of peptide agent and biodegradable polymer in solution or suspension is to keep the peptide agent and the polymer solution in two separate containers and mix them just before use. This assumes that the organic solvent may be separated from polymeric matrix quickly through diffusion, extraction or evaporation after the peptide agents and polymer solution are mixed. An example was disclosed in U.S. Pat. Nos. 6,565,874 and 6,773,714 that describe polymeric delivery formulations of leuprolide acetate that is related to a commercial product Eligard® for treatment of prostate cancer. In order to maintain the stability of the formulations, this product is supplied in separate syringes and the contents in the syringes are mixed just before use. However, because of the viscous nature of the polymer formulations, it is often difficult to mix the contents in two separated syringes by end users. The uniformity of the formulations prepared by the end-user may vary significantly where contamination may also occur and the quality of the treatment can be compromised significantly. In addition, this approach will not prevent the interaction between the peptide agent and polymer during mixing and administration. As disclosed in US20060034923 A1, when octreotide acetate was combined with polylactide-co-glicolide solution in NMP, more than 40% of octreotide was acylated within 5 hours. This modification of the peptide may lead to a significant loss of activity or change of immunogenicity. The molecular weight of the polymer also decreased significantly within the same time period. This fast degradation of the peptide and polymer will alter the release profile of the peptide and result in a compromised treatment outcome. Therefore, precise control for the preparation process and time is critical and this significantly increases the difficulty for end-user. Furthermore, the in vivo formation of the implant from the injectable polymeric composition is not instantaneous. Typically the solvent dissipation process can take a few hours to several days depending upon the solvents used. During this period, the presence of an organic solvent could also promote the interaction/reaction between the peptide agents and the polymer. Therefore, there is a need to develop a pharmaceutical composition that will minimize or prevent the interaction/reaction between the peptide agent and the polymer in an organic solution. There is a further need to develop a pharmaceutical composition that is stable with a satisfactory storage shelf life in a ready-to-use product configuration.